Lekakis, Lazaros J.

Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved for treatment of adult pts with R/R LBCL after ≥ 2 lines of systemic therapy. In the pivotal ZUMA-1 study, axi-cel demonstrated durable responses and a largely manageable safety profile (Locke FL, et al. Lancet Oncol. 2019). ZUMA-9 (NCT03153462), a multicenter, open-label study, provided pts with R/R LBCL with expanded access to axi-cel until commercial availability (Cohort 1 [C1]) and later, if commercially manufactured product did not meet commercial release specification(s) (Cohort 2 [C2]). Safety and efficacy of axi-cel (C1 and C2) and translational analyses (C2) are presented. Methods: Eligible adults had histologically confirmed R/R LBCL, ECOG ≤ 1, and received prior CD20-targeting and an anthracycline-containing regimen. C2 pts must have had commercial OOS product. Pts underwent leukaphersis and conditioning chemotherapy (cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days followed by a single axi-cel infusion (target dose, 2 × 106 CAR T cells/kg). C1 and C2 pts with high disease burden could receive bridging therapy before conditioning at investigator's discretion. Endpoints included frequency of adverse events (AEs), objective response rate (ORR) per standard-of-care imaging assessment, overall survival (OS) for C1 and C2, and blood CAR T cells levels and serum cytokines for C2 only. Outcomes were contextualized with the primary analysis of ZUMA-1 C1+2 (n = 101; ≥ 6 mo of follow-up; Neelapu SS, et al. NEJM. 2017). Results: As of 11/29/2019 (C1) and 3/15/2020 (C2), 25 C1 pts and 36 C2 pts received axi-cel with a median follow-up of 27.1 mo (range, 23.6 - 29.6) and 13.2 mo (range, 0.4 - 25.7), respectively. In C1, median age was 56 y (range, 28 - 76), 60% were male, 80% had DLBCL, 48%/0% had ECOG1/≥2, 44% had IPI ≥3, and 64% had ≥ 3 prior lines of therapy. In C2, median age was 61 y (range, 24 - 81), 75% were male, 78% had DLBCL, 58%/17% had ECOG 1/≥2, 56% had IPI ≥3, and 69% had ≥ 3 prior lines of therapy. In C2, 50% of pts had OOS product with low viability, 28% had high IFN-γ, 14% had low IFN-γ, 14% received a low dose, and 6% had high transduction ratio. The ORR was 76% (64% complete response [CR]) for C1, 53% (36% CR) for C2, and 82% (54% CR) for ZUMA-1 C1+2. Median OS was 23.8 mo (95% CI, 13.5 - NE) for C1 and not reached (95% CI, 3.4 - NE) for C2, respectively. ORR and OS were consistent in C2 OOS subgroups (Table). Grade ≥ 3 AEs were reported in 88% and 89% of C1 and C2 pts, respectively. Grade ≥ 3 CRS (Lee et al, Blood. 2014) was not observed in C1 but was reported in 3% of C2 pts (13% in ZUMA-1 C1+2). Grade ≥ 3 neurologic events (NEs) occurred in 36% and 19% of pts in C1 and C2, respectively, and 28% of pts in ZUMA-1 C1+2. No Grade 5 CRS or NEs occurred in C1 or C2. All CRS and NEs resolved in C1, and most CRS (29/30) and NEs (19/24) resolved in C2 as of the data cutoff. Of 3 Grade 5 AEs in C1, 2 were unrelated to axi-cel (clostridial sepsis [on Day (D) 6] and respiratory failure [on D212]) and 1 was related to conditioning (myelodysplastic syndrome [on D563]). Of 3 Grade 5 AEs in C2, 2 were unrelated to axi-cel (multiple organ dysfunction syndrome [on D6] and cardiac arrest [on D482]) and 1 was related to axi-cel (systemic mycosis [on D30]). Median peak CAR T cell levels and median CAR T cell expansion (area under the curve in the first 28 days) were lower in ZUMA-9 C2 (n = 32/36; 12 cells/µL [range, 0 - 442] and 112 cells/µL × days [range, 0 - 3413]) vs ZUMA-1 C1+2 (n = 96/101; 42 cells/µL [range, 1 - 1514] and 462 cells/µL × days [range, 5 - 14,329]). Serum IFN-γ levels peaked within 8 days after axi-cel infusion (median, 170 pg/mL [range, 8 - 1876]) and were lower vs ZUMA-1 C1+2 (median, 477 pg/mL [range, 8 - 8209]). Axi-cel in ZUMA-9 C2 contained fewer, less differentiated CCR7+ naïve and central memory T cells, and a greater proportion of more differentiated CCR7- effector memory and effector T cells vs ZUMA-1 C1+2. No cases of replication-competent retroviruses were reported in C1 or C2. Conclusion: Axi-cel treatment demonstrated a manageable safety profile and meaningful clinical benefit in this expanded access and OOS product study. While CAR T cell therapy showed clinical benefit in C2 (OOS product), the lower CR rate was corroborated by lower CAR T cell expansion and a more differentiated product vs ZUMA-1 C1+2, warranting further investigation. ZUMA-9 C2 is enrolling pts and evaluation is ongoing. Disclosures Jacobson: Precision Biosciences: Consultancy, Honoraria, Other: travel support; Celgene/BMS: Consultancy, Honoraria, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; AXIS: Speakers Bureau; Nkarta: Consultancy, Honoraria, Other: travel support; Clinical Care Options: Speakers Bureau; Pfizer: Research Funding; Lonza: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Locke:Calibr: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; Allogene: Consultancy. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Miltenyi Biotec: Research Funding; Janssen: Consultancy, Other: Travel support; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Vose:Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Allogene: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Miltenyi Biotec: Honoraria; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Wugen: Honoraria; Celgene: Honoraria; Roche/Genetech: Consultancy, Honoraria, Other. Lin:Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Vineti: Consultancy; Gamida Cells: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Budde:Roche: Consultancy; Merck: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding. Maloney:Celgene: Consultancy, Honoraria, Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Gilead Sciences: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jaglowski:Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy; Novartis: Consultancy, Research Funding. Riedell:MorphoSys: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Perales:Celgene: Honoraria; MolMed: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Research Funding; Miltenyi Biotec: Research Funding; Merck: Consultancy, Honoraria; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Research Funding. Kim:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kawashima:Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Neelapu:Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding; Adicet Bio: Other; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Poseida: Research Funding; Calibr: Other; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Karus Therapeutics: Research Funding; Cellectis: Research Funding; N/A: Other.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of patients (pts) with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies. ZUMA-1 is the multicenter, single-arm, registrational Phase 1/2 study of axi-cel in pts with refractory LBCL. In a 2-year analysis of ZUMA-1 (median follow-up, 27.1 months; N=101), axi-cel demonstrated objective response, complete response (CR), and ongoing response rates of 83%, 58%, and 39%, respectively (Locke et al. Lancet Oncol. 2019). Here, we present additional survival follow up and recovery of normal, polyclonal B cells from ongoing responders in ZUMA-1. Methods: Eligible pts with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis at enrollment and subsequently received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu et al. NEJM. 2017; NCT02348216). The primary endpoint was objective response rate (ORR), and the first response assessment was 4 weeks post infusion. Response assessments were performed per protocol up to 24 months or disease progression, whichever occurred first. For pts in ongoing response beyond Month 24, response assessments continued per institutional standard-of-care (SOC). Blood levels of CAR T cells were quantified using polymerase chain reaction and B cells were characterized using flow cytometry in pts with ongoing responses and evaluable samples. Results: A total of 111 pts were enrolled, and axi-cel was administered to 101 pts. As previously reported in the ZUMA-1 2-year analysis, among pts who received axi-cel, the median time from axi-cel infusion to both objective response and CR was 1.0 month (range, 1 - 12 months; Locke et al. Lancet Oncol 2019). When the entire enrolled population (N = 111) was included on an intent-to-treat basis, the median manufacturing time was 17 days (range, 14 - 51; n = 110 as manufacturing was not feasible for 1 pt). Additionally, among the 111 pts, the median time from enrollment/leukapheresis to objective response and CR was 1.7 months (range, 0.7 - 12.9) and 1.9 months (range, 0.7 - 13.3), respectively. Responses have been durable, and with a minimum of 3 years of follow-up (median, 39.1 months), the median overall survival (OS) was 25.8 months, and the 3-year OS rate was 47%. Importantly, no axi-cel-related secondary malignancies have been reported. As previously reported, pts in ongoing response after 2 years had significantly greater peak CAR T cell expansion in blood 7 - 14 days after axi-cel infusion than did those with relapse (P = 0.014) or no response (P = 0.0003; Locke et al. Lancet Oncol 2019). Blood samples from 22 pts in ongoing response (per institutional SOC) at ≥ 3 years were available for analysis of CAR T cells and evaluation of B cell recovery. All evaluable pts had detectable B cells in blood at 3 years post axi-cel. Notably, 91% of pts in ongoing response at 3-year follow-up demonstrated recovery of polyclonal B cells measured by presence of both kappa and lambda light chains on non-malignant CD19+CD20+ B cells. The median kappa-lambda ratio of 1.6 and relative levels of key B cell subsets, including memory and naive B cell immunophenotypes, suggested reconstitution of B cell repertoire, consistent with published data from healthy individuals (Deneys et al. J Immunol Methods 2001; Scott et al. J Clin Pathol 2018). Additionally, 15/22 (68%) had both minimal levels of detectable CAR gene-marked cells and detectable polyclonal B cells in blood. Altogether, these findings support the hypothesis that persistence of functional CAR T cells is not necessary for durable remissions of LBCL. Overall survival and translational findings with ≥ 4 years of follow-up will be presented. Conclusions: Axi-cel produced rapid responses and longterm disease control in pts with refractory LBCL. Most responses occurred by the first assessment, and the brief time elapsed between enrollment and response supports both the speed and success of manufacturing. Furthermore, axi-cel-treated pts with ongoing responses at ≥ 3 years showed evidence of restoration of a normal B cell compartment and clearance of functional CAR T cells, a critical component of the long-term safety of CD19-directed CAR T cell therapies. Disclosures Locke: Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ghobadi:Celegene: Consultancy; Wugen: Consultancy; Atara: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Oluwole:Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy. Lin:Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Hill:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Timmerman:Merck: Research Funding; Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Valor: Research Funding. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Reagan:Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Flinn:Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; BeiGene: Consultancy, Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Calithera Biosciences: Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Gilead Sciences: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Curis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Goy:COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Colorado Blood Cancer Institute: Current Employment; Fred Hutchinson: Patents & Royalties. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siddiqi:Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Bot:Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support . Zheng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Vezan:Merck: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. Bashir:Kite, a Gilead Company: Current Employment; OmniacPharmConsult Ltd: Current Employment, Current equity holder in private company. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Chu:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Kite, a Gilead Company: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Novartis: Other: personal fees; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees.

Abstract ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

3022 Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In ZUMA-1 (NCT02348216), the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019). T cell-related biology (Immunosign 21; Immunoscore) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel (Rossi et al. AACR 2018. #LB-016; Rossi et al. AACR 2019. #CT153). This expanded analysis characterized the pretreatment TME immune contexture and examined associations between immune cell subsets and response. Methods: In ZUMA-1, pts received axi-cel at a target dose of 2.0 × 106 CAR T cells/kg. Archival pretreatment tumor biopsy samples were analyzed by multiplex immunohistochemistry (Brightplex). Two panels were developed and applied to assess T cell (CD3, CD8, FoxP3, PD-1, LAG-3, TIM-3) and myeloid cell (CD11b, CD14, CD15, LOX1, S100A9, CD68) subsets (n = 14 total). The association between T cell and myeloid cell subset density, prespecified immune scores (Immunosign 21; Immunoscore), and objective response was evaluated. T test values were based on Brightplex analysis. Results: Pretreatment tumor biopsy samples from 18 pts were analyzed (14 objective responders and 4 nonresponders). The pretreatment TME comprised all major myeloid and T cell subsets, with diverse distribution across samples analyzed. The median TME density of monocytes (CD11b+ CD15− CD14+; 1215 cells/mm2) and macrophages (CD68+; 530 cells/mm2) was greater than that of the total CD8+ T cell subset (312 cells/mm2). The pretreatment Immunosign 21 and Immunoscore scores associated positively with the density of all major T cell subsets and some myeloid subsets. The density of activated CD8+ T cells (PD-1+ LAG-3+/− TIM-3−) was most significantly associated with clinical response versus other T cell subsets. The density of nonactivated CD8+ T cells (PD-1− LAG-3− TIM-3−) and exhausted CD8+ T cells (PD-1+ LAG-3+ TIM-3+) were not significantly associated with response. Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusions: These results suggest that a TME associated with increased density of activated PD-1+ LAG-3+/− TIM-3− CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post–axi-cel.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication. PATIENTS AND METHODS Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution’s guidelines. Responses were assessed as per Lugano 2014 classification. RESULTS Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel–treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis. CONCLUSION The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

Introduction: Axicabtagene Ciloleucel (axi-cel), a CD19 chimeric antigen receptor (CAR) T-cell therapy, was approved for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma in October, 2017. In the ZUMA-1 trial leading to axi-cel FDA approval, patients (pts) with prior or active secondary central nervous system (CNS) lymphoma involvement were excluded. A recent publication of 8 pts with secondary CNS lymphoma who underwent Tisagenlecleucel CAR T cell therapy was reported (Frigault M.J.2019). Since the two FDA approved CAR T cell products have a different neurotoxicity profile, understanding outcomes of axi-cel in this setting is important. We report here the real-world experience of 17 pts treated with axi-cel who had a history of secondary CNS involvement or had active CNS disease at time of CAR T infusion. Methods: Seventeen academic centers from the US Lymphoma CAR T Consortium contributed data independently from the manufacturer. Data regarding secondary CNS involvement, management, and outcome were obtained in addition to CAR T therapy outcome for pts who were identified as having active, secondary CNS involvement at the time of evaluation for CAR-T therapy. Nine centers reported data on 17 cases with CNS involvement. Follow-up data was missing for one pt in the CNS cohort. Lee criteria or the modified Lee grading scale were used for cytokine release syndrome (CRS). CTCAEv4 or CARTOX grading were used for immune effector cells associated neurotoxicity syndrome (ICANS). All leukapheresed pts were included in the intention to treat (ITT) analysis for response rate and event-free survival (EFS). EFS was defined as date of leukapheresis until progression or death due to any cause. EFS was evaluated using Kaplan Meier curves with log-rank test. Differences in clinical characteristics and response between CNS and non-CNS pts were not formally tested due to small sample size and multiple comparison concerns. Results: With a data cut-off of 4/30/2019, 300 pts underwent leukapheresis with intention to manufacture standard of care axi-cel. By the time of leukapheresis, 17 (6%) had secondary CNS involvement (4 parenchymal disease, 10 leptomeningeal/CSF, 3 data not available). Compared to the non-CNS cohort, baseline demographics were comparable (Panel A). Manufactured axi-cel was within specification for 100% of the CNS cohort. There was a higher rate of bridging therapy use in the CNS cohort 82% (1 steroids only, 2 radiation therapy, 12 systemic therapy) vs 52% in non-CNS cohort; p=0.022. Time from leukapheresis to CAR T infusion was 3.5 days longer in the CNS cohort as opposed to the non-CNS cohort: median time of 29.5 (range 20-76) vs. 26 days (range 5-67), (p=0.029), respectively. The CAR T infusion rate was 88% for the CNS cohort (15/17) compared to 93% (262/283) in the non-CNS cohort. Among the 15 infused pts in the CNS cohort, 10 had resolution of CNS involvement, and 5 had persistent active CNS disease at time of CAR T infusion. After axi-cel infusion, the incidence of CRS and ICANS, of any grade or grade 3 or higher, were comparable between the CNS and non-CNS cohorts. Tocilizumab and steroid use were comparable between the two groups (Panel B). No seizures or cerebral edema were noted in the CNS cohort. With a median follow-up of 10.1 months from leukapheresis (range 7.6-12.6), the ITT best overall response rates (CR+PR) and ongoing responses at month 6 between CNS and non-CNS cohorts were 75% vs. 59%, and 41% vs. 31%, respectively (Panel B). In the 5 pts with active CNS disease at time of CAR T infusion, the response of CNS disease were 2 CR, 1 PR and 2 PD as best response. In the 10 pts with resolved CNS disease at time of CAR T infusion, 2 PD were seen and both occurred systemically. EFS from leukapheresis was not statistically significantly different between CNS and non-CNS cohorts (6 months EFS: CNS cohort, 36%; non-CNS cohort 57%. HR=1.58, 95% CI: 0.83-3.01, p=0.16, Panel C). Six month EFS from the date of infusion for the CNS cohort was 49.9% (Panel D). Conclusions: Pts attempting CAR T therapy with secondary CNS disease in the real world setting had similar rates of CAR T infusion, toxicity, and outcomes when compared to patients without CNS disease. Small sample size and limited follow-up caution the strength of conclusions for application to clinical practice, but these results support further investigation of CAR T in pts with history of or active secondary CNS lymphoma. Figure Disclosures Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Nastoupil:Bayer: Honoraria; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Jain:Kite/Gilead: Consultancy. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cashen:Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Goy:COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Vu:Celgene: Other: Stock. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy. Munoz:Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Neelapu:Unum Therapeutics: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; Poseida: Research Funding; Allogene: Consultancy; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Acerta: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy. Lin:Novartis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBird Bio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees.

MDJ and MTJ contributed equally; FLL and AG contributed equally. Introduction Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are autologous anti-CD19 CAR T-cell therapies approved for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) who have failed at least two lines of systemic therapy. In the ZUMA-1 trial that led to axi-cel approval, the median time between apheresis and delivery of CAR T cells to the treating facility was 17 days (Neelapu, Locke et al. NEJM 2018). Bridging therapy, defined as lymphoma therapy given between apheresis and the start of lymphodepleting chemotherapy, was not permitted on ZUMA-1. By contrast, the pivotal JULIET trial for tisa-cel (Schuster et al. NEJM 2019) had a median time from enrollment to infusion of 54 days and 92% of patients received bridging therapy. Whether bridging therapy affects lymphoma CAR T outcomes is unknown. Here we evaluate patients receiving bridging therapy for axi-cel in a large multicenter cohort. Methods and Results The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data from lymphoma patients treated with standard of care (SOC) CAR T-cell therapy independently of manufacturers. As of 8/31/2018, 300 patients were apheresed with intent to manufacture SOC axi-cel for LBCL. Of the 23 patients that underwent apheresis for axi-cel and did not receive it, 20 had lymphoma progression or death that precluded CAR T infusion, of which 16 received bridging therapy. In this study, we analyze the modified intent-to-treat (mITT) population of 276 patients receiving CAR T infusion with a median follow up of 9 months. In this group, 146 (53%) patients received bridging therapy while 130 (47%) patients received no bridging therapy. Bridging therapy consisted of steroids alone (n = 35, 24%), chemotherapy (n = 73, 50%), radiation (n = 24, 16%), or targeted therapies (n = 14, 10%). At baseline, a higher proportion of patients in the bridging therapy group had an ECOG score of 2 - 4 vs. 0 - 1 (bridging 24.8%, no bridging 6.1%, p <0.001), IPI score of 3 -5 vs. 0 - 2 (bridging 67.6%, no bridging 34.3%, p <0.001), bulky disease greater than 10 cm (28.2% vs. 13.0%, p = 0.002), immunohistochemical double expression of MYC and BCL2 (42.5% vs. 24.6%, p =0.004) and would not have met all the eligibility criteria for ZUMA-1 for reasons other than bridging therapy (48.6% vs. 30.0%, p = 0.002). After axi-cel infusion, patients in the bridging group had similar rates of severe (grade 3 or higher) cytokine release syndrome (CRS) (8.2% vs. 5.3%, p = 0.34) and ICANS (35.2% vs. 28.2%, p = 0.25). However, the rate of ICU admission was higher in the bridging group (41.4% vs. 22.9%, p = 0.001) as was median length of hospital stay (15 vs. 14 days, p = 0.02). While data on cytopenias was not collected, use of G-CSF after CAR T therapy was higher in the bridging group (48.2% vs. 32.1%, p = 0.006). In terms of outcomes, in multivariate analysis correcting for confounding features, there was no statistically significant difference in overall response rate (p = 0.2), complete response rate (p = 0.19), and progression free survival (p = 0.3) between bridging and no bridging groups; but bridging therapy was associated with significantly poorer overall survival (p = 0.001) and lymphoma specific survival (p = 0.019) (figure 1.). Both death due to lymphoma (33.1% vs. 13.0%) and death due to treatment-related mortality (TRM) (6.9% vs. 1.5%) were higher in the bridging group (p <0.001). Conclusions Lymphoma patients receiving bridging therapy had poorer prognostic factors at baseline and after axi-cel infusion experienced decreased lymphoma-specific and overall survival compared with patients with no bridging. This inferior outcome raises the possibility that bridging therapy may identify a sub-group of lymphoma patients with a different biology, or alternatively, bridging therapy may have an effect on the host or the tumor microenvironment that may impact CAR-T efficacy. With or without bridging, 7% of patients in our series did not receive axi-cel due to lymphoma progression and/or death. In addition, there may have been patients where bridging prevented progression or death prior to axi-cel infusion. Prospective evaluation of different bridging strategies is warranted to determine if any can improve outcomes after axi-cel, and/or if they should be utilized only for patients requiring emergent disease control during the manufacture period. Disclosures Jain: Kite/Gilead: Consultancy. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Lin:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBird Bio: Research Funding; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sorrento: Membership on an entity's Board of Directors or advisory committees. Lunning:Curis: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Bayer: Consultancy; DAVA: Consultancy; Gilead Sciences, Inc.: Consultancy; Kite: Consultancy; Novartis: Consultancy; OncLive: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Goy:University of Nebraska: Research Funding; Hakensackumc: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; Genentech: Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; TG therapeutics: Research Funding; Amgen: Research Funding. Munoz:Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Neelapu:Cellectis: Research Funding; Allogene: Consultancy; Incyte: Consultancy; BMS: Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Acerta: Research Funding; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Bennani:Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Andreadis:Pharmacyclics: Research Funding; Novartis: Research Funding; Roche: Equity Ownership; Celgene: Research Funding; Juno: Research Funding; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Employment; Merck: Research Funding; Gilead: Consultancy; Kite: Consultancy. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.

Background Although rituximab‐based high‐dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto‐HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab‐based conditioning on auto‐HCT outcomes in patients who have DLBCL. Methods Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto‐HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab‐containing chemoimmunotherapy and had chemosensitive disease pre‐HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS). Results The study cohort was divided into 2 groups: BEAM (n = 667) and R‐BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS ( P = .83) or progression‐free survival (PFS) ( P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse ( P = .15) or nonrelapse mortality ( P = .12) was observed. Variables independently associated with lower OS included older age at auto‐HCT ( P < .001), absence of CR at auto‐HCT ( P < .001) and early chemoimmunotherapy failure ( P < .001). Older age ( P < .0002) and non‐CR pre‐HCT ( P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts. Conclusion In this large registry analysis of DLBCL patients undergoing auto‐HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto‐HCT, and early chemoimmunotherapy failure were associated with inferior survival.

M.T.J. and M.D.J. contributed equally; A.G. and F.L.L. contributed equally. Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy that is approved for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) who have failed at least two prior systemic lines of therapy. In the ZUMA-1 trial that led to axi-cel approval, 93% of patients developed cytokine release syndrome (CRS) (Neelapu, Locke et al. NEJM 2018). CRS is a non-antigen-specific toxicity that occurs as a result of CAR T and bystander immune cell activation. Whether lack of development of CRS after treatment with axi-cel is associated with inferior lymphoma outcomes is unknown. Here we evaluate the outcomes of patients that did not develop CRS after receiving axi-cel in a large multicenter cohort. Methods and Results The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. As of 8/31/2018, 300 patients were apheresed with intent to manufacture standard of care axi-cel for LBCL. In this study, we analyzed the modified intent-to-treat (mITT) population of 276 patients receiving CAR T infusion with a median follow up of 9 months. In this group, 25 patients (9%) did not develop CRS and 251 patients (91%) developed CRS following axi-cel infusion. CRS was graded according to Lee criteria (Lee et al. Blood 2014) or CARTOX (Neelapu SS et al. Nat Rev Clin Oncol. 2018). At baseline, a higher proportion of patients in the no CRS group had ECOG score of 0-1 (no CRS group 100% vs. CRS group 82%, p= 0.019) and IPI score of 0-2 (no CRS group 72% vs. CRS group 46%, p = 0.019) After CAR T cell infusion, patients who did not develop CRS had a lower chance of developing grade 3 or higher neurotoxicity (no CRS group 4% vs. CRS group 35%, p=0.001), lower rates of ICU admission (no CRS group 8% vs. CRS group 35%, p = 0.006), and shorter length of hospital stay (median 10 days for no CRS group vs 14 days for CRS group, p &lt; 0.001). Of the 25 patients who had grade 0 CRS, 23 (92%%) also had grade 0 neurotoxicity. In univariate analysis, no CRS was associated with lower complete response (CR) rate (no CRS group 40% vs. CRS group 66%, p=0.015) but no statistically significant difference in overall response rate (ORR) (no CRS group 72% vs. CRS group 84%, p= 0.158). In relation to CRS there was no difference in treatment related mortality among the two groups (CRS group 4% vs. no CRS group 4.4%, p = 0.85). In multivariate analysis correcting for confounding features, no CRS was associated with statistically significant lower complete response rate (p = 0.002), but there was no significant difference in ORR (p = 0.13), overall survival (P=0.15), progression free survival (P=0.16), and time to progression (P= 0.14) between the two groups (figure 1.). Conclusions In this large cohort of LBCL patients receiving axi-cel with median follow up of 9 months, patients that did not develop CRS, compared with those that developed CRS, achieved lower rates of complete response but there was no difference in overall response rate, progression free survival, time to progression, overall survival, and treatment related mortality between the two groups. Disclosures Jain: Kite/Gilead: Consultancy. Nastoupil:Bayer: Honoraria; TG Therapeutics: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Spectrum: Honoraria. Lunning:Spectrum: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; VANIUM: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Novartis: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding. Deol:Agios: Other: Advisory board; Novartis: Other: Advisory board; Kite: Other: Advisory board. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hakensackumc: Research Funding; Hackensack University Medical Center, RCCA: Employment; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding. Hill:Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding. Andreadis:Juno: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Roche: Equity Ownership; Jazz Pharmaceuticals: Consultancy; Kite: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Employment; Pharmacyclics: Research Funding; Merck: Research Funding. Munoz:Incyte: Research Funding; Portola: Research Funding; AstraZeneca: Speakers Bureau; Fosunkite: Speakers Bureau; Pfizer: Consultancy; Alexion: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bennani:Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Becton Dickinson: Research Funding; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Neelapu:Poseida: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Allogene: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; BMS: Research Funding; Merck: Consultancy, Research Funding; Karus: Research Funding. Ghobadi:Wugen: Consultancy; Celgene: Consultancy; EUSA: Consultancy; Kite Pharma a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor.